Fig 3.

Stresses common in the tumor microenvironment can inhibit NMD via eIF2α phosphorylation. During tumor growth hypoxia and amino acid deprivation occur (top). Both of these stresses lead to eIF2a phosphorylation through the PERK and GCN2 kinase, respectively, which then inhibits NMD. The inhibition of NMD can then not only stabilize mutated tumor suppressor genes, but up-regulate a variety of cellular transcripts, including those important for the cellular response to amino acid starvation and ER stress, which then promote tumor adaptation and growth. The inhibition of NMD may also disversify the transcriptome through the stabilization of alternatively spliced isoforms (see Fig 2).